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Objective:To evaluate the efficacy and safety of cilomilast therapy for Chronic Obstructive Pulmonary DiseaseBackground:COPD is a common disease which is usually characterized by partially reversible airflow limitation, progressive loss of lung function and an abnormal inflammatory response in the lung to noxious substances, the most common of which is cigarette smoke. The disease is associated with increased frequency of exacerbations and deterioration of health status, as well as the development of non pulmonary complications. The pathogenesis of COPD remains unclear but chronic inflammation throughout airways, parenchyma and pulmonary vasculature is believed to have a central role. There is a need for a novel anti-inflammatory treatment, as experimental data indicate that the inflammatory process in COPD, particularly those that are neutrophil mediated, may be resistant to the anti-inflammatory effects of corticosteroids.Novel anti-inflammatory therapies are therefore being developed as potential therapeutic agents, including selective phosphodiesterase (PDE) inhibitors. Cilomilast is a potent and selective PDE4 inhibitor which modulates pathophysiological processes of direct relevance to COPD. In preclinical studies,cilomilast relaxed airway smooth muscle, inhibited immune and inflammatory cell activation and inhibited cellular infiltration and mediator release. The effect of cilomilast on airway cells was evaluated using bronchial epithelial cells and induced sputum cells (squamous and immune cells) from COPD patients, normal controls and smokers. Cilomilast significantly reduced TNFa release by bronchial epithelial and sputum cells, and GM-CSF release by sputum cells. Supernatants of sputum and bronchial epithelial cells treated with cilomilast also demonstrated significantly reduced neutrophi chemotaxis. Furthermore, cilomilast attenuatedthe inhaled lipopolysaccharide-induced pulmonary neutrophilia and oedema with equivalent effectiveness to that of high-dose, orally administered prednisolone in an animal model. This suggested a possible beneficial role for cilomilast on the neutrophilic inflammation in COPD. Since 1999, there was a series clinical research designed to explore the effectiveness and safety of the cilomilast treatment of chronic obstructive pulmonary disease, but the results were quite conflicting. The objective of the present meta-analysis was to evaluate the efficacy and safety of cilomilast in COPD.Methods:We searched the CochraneLibrary(Issuel,2011), MEDLNE(1966 to February,2011), EMBASE(1984 to 2011), the China Biological Medicine Database(1978 to February,2011), VIP(1977 to February,2011), CMAC(1994 to 2011)and hand-searched several related Chinese journals.Two reviewers independently screened the studies for eligibility, evaluated the quality and extracted the data from the eligible studies, with the confirmation of cross-check. Different opinions would be decided by the third party. The quality of the included trials such as randomization, blind, allocation concealment and following-up was assessed.Meta-analysis was Performed by RevMan5.1 software. After heterogeneity test, data without heterogeneity could be pooled using fixed effect model, and those with Heterogeneity could be solved by sensitivity analysis, subgroup analysis as well as randomized effect model. We will compare outcome measures for binary data using relative risks(RR) or odds ratio(OR) with 95% confidence intervals(Cl).For continuous data, the weighted means difference(WMD) or standardlzed mean difference (SMD) will be used.Results:sixteen studies involving 6910 patients with Chronic Obstruetive Pulmonary Disease were included. Results suggested that In terms of lung function FEV1 in patients with COPD can be improved by cilomilast therapy, SMD:0.20, 95%CI[0.11,0.30], P<0.0001; FVC in patients with COPD can be improved by cilomilast therapy, WMD:0.07,95%CI[0.02,0.11], P=0.003; FEV1% pred in patients with COPD can be improved by cilomilast therapy; FVC% pred in patients with COPD can be improved by cilomilast therapy; RV% pred in patients with COPD can be improved by cilomilast therapy; RV/TLC in patients with COPD can be improved by cilomilast therapy; FRC in patients with COPD can not be improved by cilomilast therapy, SMD:-0.20,95%CI[-0.48,0.08], P=0.16; RV in patients with COPD can not be improved by cilomilast therapy, SMD:-0.23,95%CI[-0.65,0.19], P=0.29; PEF in patients with COPD can not be improved by cilomilast therapy; IC in patients with COPD can not be improved by cilomilast therapy。In terms of health status, SGRQ in patients with COPD can not be improved by cilomilast therapy, SMD:-0.08,95%CI[0.11,0.30], P=0.13; Borg scale in patients with COPD can not be improved by cilomilast therapy, WMD:-0.06,95%CI[-0.25,0.13]; Summary symptom score in patients with COPD can not be improved by cilomilast therapy,WMD:-0.06, 95%CI[-0.25,0.13], P=0.53; Six-minute walk in patients with COPD can not be improved by cilomilast therapy, SMD:0.15,95%CI[-0.35,0.04], P=0.12;COPD exacerbation rates in patients with COPD can not be decreased by cilomilast therapy,OR:1.26,95%CI[0.95,1.67], P=0.23;Level 2 and level 3 COPD exacerbation rates in patients with COPD can not be decreased by cilomilast therapy, OR:1.40, 95%CI[0.81,2.43], P=0.10。In terms of adverse reactions, The occurrence of AE events increased in treatment group than in the control group,OR:1.34,95%CI[1.09, 1.64], P=0.005; There were no significant differences between treatment group and control group in the SAE events, OR:0.92,95%CI[0.74,1.12], P=0.42; The occurrence of nausea events increased in treatment group than in the control group,,OR:3.59,95%CI[2.84,4.55].P<0.0001; The occurrence of diarrhea events increased in treatment group than in the control group, OR:2.51,95%CI[2.04,3.09], P<0.0001; The occurrence of abdominal pain events increased in treatment group than in the control group, OR:2.03,95%CI[1.55,2.66], P<0.0001; The occurrence of vomitting events increased in treatment group than in the control group,, OR:4.80,95%CI[3.24,7.09], P<0.00001; There were no significant differences between treatment group and control group in the headache events, OR:1.27, 95%CI[1.03,1.56], P=0.03,; The occurrence of dizziness events increased in treatment group than in the control group OR:1.88,95%CI[1.10,3.21], P=0.02,; There were no significant differences between treatment group and control group in the upper respiratory tract infection events, OR:1,95%CI[0.79,1.27], P<0.00001; The occurrence of dyspepsia events increased in treatment group than in the control group OR:2.94,95%CI[2.11,4.10], P<0.00001.Conclusions:Results suggested that In terms of lung function FEV1 in patients with COPD can be improved by cilomilast therapy; FVC in patients with COPD can be improved by cilomilast therapy; FEV1% pred in patients with COPD can be improved by cilomilast therapy; FVC% pred in patients with COPD can be improved by cilomilast therapy; RV% pred in patients with COPD can be improved by cilomilast therapy; RV/TLC in patients with COPD can be improved by cilomilast therapy; FRC in patients with COPD can not be improved by cilomilast therapy; RV in patients with COPD can not be improved by cilomilast therapy; PEF in patients with COPD can not be improved by cilomilast therapy; IC in patients with COPD can not be improved by cilomilast therapy。In terms of health status, SGRQ in patients with COPD can not be improved by cilomilast therapy; Borg scale in patients with COPD can not be improved by cilomilast therapy; Summary symptom score in patients with COPD can not be improved by cilomilast therapy; Six-minute walk in patients with COPD can not be improved by cilomilast therapy;COPD exacerbation rates in patients with COPD can not be decreased by cilomilast therapy;Level 2 and level 3 COPD exacerbation rates in patients with COPD can not be decreased by cilomilast therapy。In terms of adverse reactions, The occurrence of AE events increased in treatment group than in the control group; There were no significant differences between treatment group and control group in the SAE events,; The occurrence of nausea events increased in treatment group than in the control group,; The occurrence of diarrhea events increased in treatment group than in the control group.; The occurrence of abdominal pain events increased in treatment group than in the control group,; The occurrence of vomitting events increased in treatment group than in the control group,,; There were no significant differences between treatment group and control group in the headache events; The occurrence of dizziness events increased in treatment group than in the control group; There were no significant differences between treatment group and control group in the upper respiratory tract infection events,; The occurrence of dyspepsia events increased in treatment group than in the control group。
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